Published papers

Despite similar traditional risk factors, morbidity and mortality rates from coronary heart disease in western and non-western cohorts remain substantially different. Careful study of such cohorts may help identify novel risk factors for CHD, and contribute to the formulation of new preventive strategies.

Objective. In a population with a markedly lower coronary mortality such as in Japan, the benefit of cholesterol screening may be different from Western populations. We attempted to assess the importance of cholesterol screening in Japan. Design. A 13.2-year cohort study for cause-specific mortality. Setting. Three hundred randomly selected districts throughout Japan in which the National Survey on Circulatory Disorders 1980 was performed. Subjects. A total of 9216 community dwelling persons aged 30 years and over, with standardized serum cholesterol measurement and without a past history of cardiovascular disease. Results. There were 1206 deaths, which included 462 deaths due to cardiovascular disease with 79 coronary heart diseases. Hypercholesterolemia (>6.21 mmol L-1) showed a significant positive relation to coronary mortality (relative risk; 2.93, 95% confidence interval: 1.52-5.63) but not to stroke. Although hypocholesterolemia (<4.14 mmol L-1) was significantly associated with an increased risk of liver cancer, noncardiovascular, noncancer disease and all-cause mortality, these associations, except for liver cancer, disappeared after excluding deaths in the first 5 years of the follow-up. The multivariate adjusted attributable risk of hypercholesterolaemia for coronary disease was 0.98 per 1000 person-years, which was three-fold higher than that of hypocholesterolemia for liver cancer: 0.32 per 1000 person-years. The attributable risk percentage of hypercholesterolaemia was 66% for coronary heart disease. Conclusion. Similar to Western populations, it is recommended to provide screening for hypercholesterolaemia in Japan, especially for males, although its attributable risk for coronary disease might be small.

In order to estimate the salt and potassium intake in a population and to compare their annual trends, we developed a simple method to estimate population mean levels of 24-h urinary sodium (24HUNaV) and potassium (24HUKV) excretion from spot urine specimens collected at any time. Using 591 Japanese data items from the INTERSALT study as a gold standard, we developed formulas to estimate 24-h urinary creatinine (24HUCrV), 24HUNaV and 24HUKV using both spot and 24-h urine collection samples. To examine the accuracy of the formulas, we applied these equations to 513 external manual workers. The obtained formulas were as follows: (1) PRCr (mg/day) = -2.04 × age + 14.89 × weight (kg) + 16.14 × height (cm) - 2244.45; (2) estimated 24HUNaV (mEq/day) = 21.98 × XNa0.392; (3) estimated 24HUKV (mEq/day) = 7.59 × XK0.431; where PRCr = predicted value of 24HUCr, SUNa = Na concentration in the spot voiding urine, SUK = K concentration in the spot voiding urine, SUCr = creatinine concentration in the spot voiding urine, XNa (or XK) = SUNa (or SUK)/SUCr × PRCr. In the external group, there was a significant but small difference between the estimated and measured values in sodium (24.0 mmol/day) and potassium (3.8 mmol/day) excretion. In every quintile divided by the estimated 24HUNaV or 24HUKV, the measured values were parallel to the estimated values. In conclusion, although this method is not suitable for estimating individual Na and K excretion, these formulas are considered useful for estimating population mean levels of 24-h Na and K excretion, and are available for comparing different populations, as well as indicating annual trends of a particular population.

Moderate drinkers with a defective alcohol dehydrogenase type 3 (ADH3) genotype have higher high-density lipoprotein (HDL) levels and a decreased risk of coronary artery disease (CAD). We examined the interaction between the aldehyde dehydrogenase type 2 (ALDH2), alcohol intake, and HDL levels in 826 men and 1295 women in a rural town in Japan. The ALDH2 genotype of each subject was determined by polymerase chain reaction (PCR) analysis. HDL was adjusted for the alcohol intake, age, body mass index, smoking status, total cholesterol, triglycerides and HbA1c levels. None of the subjects had a history or ECG suggestive of CAD. The proportions of ALDH2, *1/*1, *1/*2, and *2/*2 (defective homozygote) were 45.8, 46.0, and 8.2%, respectively, for men. Drinking more than two drinks daily was associated with lower HDL levels in men with the defective genotypes compared with men with a normal genotype (55.6±0.9 vs. 51.2±0.9 mg/dl, mean±S.E., P<0.0001). Also, drinking more than 0.5 drinks daily was not associated with beneficial effects on HDL levels in women with defective ALDH2 genotypes. Conclusions: Alcohol intake did not have beneficial effects on HDL levels in the defective ALDH2 genotype and may not protect against CAD in subjects with defective ALDH2 genotypes. © 2002 Elsevier Science Ireland Ltd. All rights reserved.

Background and Purpose - The role of serum fatty acids as a risk factor for stroke and stroke subtypes is largely unknown. Methods -A prospective nested case-control study of Japanese 40 to 85 years of age was conducted through the use of frozen serum samples from 7450 participants in cardiovascular risk surveys collected from 1984 to 1989 for 1 community and 1989 to 1992 for the other 2 communities. By the end of 1998, we identified 197 incident strokes whose subtypes were confirmed by imaging studies. Three controls per case were selected by matching for sex, age, community, year of serum storage, and fasting status. Results - Compared with controls, total (n=197), hemorrhagic (n=75), and ischemic (n=122) strokes had similar proportions of n3 polyunsaturated fatty acids, lower proportions of linoleic and arachidonic acids, and higher proportions of saturated and monosaturated acids, determined by gas chromatography. The multivariate odds ratios associated with a 1-SD increase in linoleic acid (5%) after adjustment for hypertension, diabetes, serum total cholesterol, and other cardiovascular risk factors were 0.72 [95% confidence interval (CI), 0.59 to 0.89] for total stroke, 0.66 (95% CI, 0.49 to 0.88) for ischemic stroke, 0.63 (95% CI, 0.46 to 0.88) for lacunar infarction, and 0.81 (95% CI, 0.59 to 1.12) for hemorrhagic stroke. The respective odds ratios for saturated fatty acids (4%) were 1.13 (95% CI, 1.05 to 1.65), 1.35 (95% CI, 1.01 to 1.79), 1.44 (95% CI, 1.03 to 2.01), and 1.21 (95% CI, 0.82 to 1.80). Further adjustment for other fatty acids attenuated these relations, but the relation between linoleic acid and risk of ischemic stroke remained statistically significant. Conclusions - A higher intake of linoleic acid may protect against ischemic stroke, possibly through potential mechanisms of decreased blood pressure, reduced platelet aggregation, and enhanced deformability of erythrocyte cells.

To investigate the association of lifestyle and constitutional variables with platelet aggregation, we examined the platelet aggregation, serum fatty acid composition, alcohol intake, smoking, and dietary intake of seafood and soybean estimated by a 1-week dietary record in 448 males aged 50-70 in three rural Japanese communities: Ikawa, Akita prefecture (northeast coast), Noichi, Kochi prefecture (southwest coast), and Kyowa, Ibaraki prefecture (central inland). Platelet aggregatory threshold index (PATI) was used to determine the minimum concentration of adenosine 5′-diphosphate (ADP) that caused a non-reversible aggregation of platelets. Intake of seafood and n3-polyunsaturated fatty acid and ingestion of ethanol were higher in the northeast coastal community than in the other two communities. Mean platelet and white blood cell counts were lower in northeast coastal community than in the other two communities. The geometric mean PATI was higher (i.e. platelet aggregation was lower) in the northeast coastal community than the other two communities. Within the entire sample, platelet aggregation correlated inversely with serum level of n3-polyunsaturated fatty acids and γ-glutamyl transpeptidase, an index of alcohol consumption, and positively with platelet and white blood cell counts. Platelet aggregation tended to correlate positively with serum arachidonic acid. There was no correlation between smoking and platelet aggregation. Our results suggest that seafood intake and moderate alcohol consumption reduce platelet aggregation. © 2002 Elsevier Science Ireland Ltd. All rights reserved.

In Japanese and other Asians, the prevalence of genetically decreased mitochondrial aldehyde dehydrogenase (ALDH2) activity is higher than in Caucasians. The aim of this study was to elucidate the relation between ALDH2 genotypes and blood pressure levels or hypertension in Japanese. After obtaining informed consent for genetic analysis from 917 men and 1,478 women who lived in a mountainous farming region near Kyoto and who were free from cardiovascular disease and liver dysfunction, the authors identified the ALDH2 genotype in all subjects. Differences in blood pressure level among genotypes were then compared by analysis of covariance, and the relation between genotypes and hypertension was also analyzed by logistic regression analysis. The frequencies of genotypes *1/*1, *1/*2, and *2/*2 were 44.7%, 46.9% and 8.4% in men, and 50.1%, 43.2% and 6.8% in women, respectively. In men, systolic and diastolic blood pressures tended to decrease in the order of *1/*1>*1/*2>*2/*2. However, adjustment for confounding factors including alcohol consumption resulted in the disappearance of significance. Logistic regression analysis adjusted for the same confounding factors for men showed that the odds ratios (OR) of being hypertensive in the *2 allele to not having *2 allele were 0.67 (95% confidence interval (CI): 0.47-0.96). However, in the subgroup analyses, this relation was not observed in the group having a below-median level of alcohol consumption (OR=0.92; 95% CI: 0.53-1.62) or in the group not taking antihypertensive agents (OR=0.77; 95% CI: 0.52-1.15). Furthermore, we did not observe any relation between the ALDH2/*2 allele and hypertension in women (OR=1.07; 95% CI: 0.80-1.42). The results suggest that there may be no causal relation between hypertension and the ALDH2 genotype per se, after excluding for some confounding factors, especially for alcohol drinking.

Recent studies have described a linkage between angiotensin converting enzyme (ACE) gene polymorphism and hypertension in a large number of hypertensive sibs. Moreover, among Japanese, the DD genotype of the ACE gene has been reported to be a genetically predisposing factor for hypertension in a large general population. However, there is some controversy regarding the association between the ACE insertion/deletion (I/D) polymorphism and systemic hypertension. Therefore, we examined the influence of the ACE I/D polymorphism in a random Japanese population. The participants were 2,892 subjects (1,110 males: mean age, 58.4±15.5; 1,782 females: mean age, 56.2±15.7) who underwent medical examinations in 1999 in Shigaraki, a suburban town located in an urban area in Shiga prefecture. Among them, 2,395 subjects (917 males: mean age, 58.0±15.7; 1478 females: mean age, 56.3±15.6) who gave their informed consent for genetic analysis were enrolled in the present study. Every year since 1991, we have repeatedly performed medical examinations in Shigaraki. ACE genotypes were determined by polymerase chain reaction (PCR) methods. Logistic analysis revealed that age (p<0.001; odds ratio=1.091), body mass index (BMI) (p<0.001; odds ratio=1.211), and family history of hypertension (p<0.001; odds ratio=0.371) were associated with hypertension (systolic blood pressure greater than 140 mmHg and diastolic greater than 90 mmHg). There was no association between ACE polymorphism and blood pressure. There were also no significant differences in blood pressure among males or females across the three genotypes. Moreover, in an analysis of 1,484 subjects (549 males: mean age, 62.8±12.1; 935 females: mean age, 61.2±12.6) who were followed-up since 1991, there was no association between ACE polymorphism and changes in blood pressure (p=0.3905). We conclude that ACE polymorphism does not appear to have any significant association with blood pressure, changes in blood pressure or sex in Japanese subjects, who have a more homogeneous genetic background than any other group reported to date.

High plasma homocysteine, a risk factor for atherosclerosis, is frequently caused by a common mutation in the gene for the enzyme, 5,10-methylenetetrahydrofolate reductase (MTHFR), C677T (alanine to valine substitution) or low intake of B vitamins that affect the remethylation or transsulfuration pathways in homocysteine metabolism. However, the interaction of the C677T mutation and B vitamins other than folate has not been well elucidated. We conducted a cross-sectional survey of 324 men and 641 women who participated in a 1996 health examination under a hypothesis that high nutritional status of folate, vitamin B12 and vitamin B6 expressed as high serum levels, may compensate for the hyperhomocysteinemia associated with homozygosity for the C677T mutation, but not for having the mutation per se. Age-adjusted plasma homocysteine levels were higher for both men and women with the homozygous genotype for the mutation than those who were heterozygous or had no mutation. Elevated homocysteine levels in homozygous genotype was attenuated among persons with higher serum levels of vitamin B12 and folate, but not vitamin B6, and among persons with the combination of lower folate and higher vitamin B12 and of higher folate and higher vitamin B12, split by the median. These findings suggest that elevated homocysteine levels among Japanese with the homozygous genotype for the MTHFR gene mutation can be modified efficiently by dietary supplement of vitamin B12 as well as folate. © 2002 Elsevier Science Ireland Ltd. All rights reserved.

An inverse association between blood cholesterol level and excess mortality in low cholesterol level subjects has been reported, but there has been no reasonable explanation widely accepted. To evaluate the associations between unfavorable factors and low blood cholesterol in non-Western populations, we performed a cross-sectional study in a rural Japanese population. A self-administered questionnaire concerning health characteristics and a nutritional survey, using a continuous 48-hour dietary record, was conducted on 461 males and 571 females aged 20-79 years old. The serum total cholesterol (TC) of less than 160 mg/dl was defined as low cholesterol, which accounted for 18% of the subjects. The multivariate odds ratio of having low cholesterol adjusted for age and selected variables were 0.70 (95% Cl: 0.52-0.94) for 1SD increment of Key's lipid factor, 0.71 (0.51-0.97) for 1SD increment of vitamin A intake, 2.23 (1.01-4.91) for heavy drinking, 2.80 (1.21-6.46) for being underweight and 2.59 (1.01-6.61) for blood transfusion in males, and 1.04 (1.00-1.08) for 10 cigarette-year increase in smoking in females. Even when further adjusted for body mass index, these associations were still significant except for those who were underweight and had undergone blood transfusion in males. These findings may partly explain the excess mortality of the Japanese males with low serum TC.

To calculate the estimated relative and absolute risks for cardiovascular diseases according to alcohol consumption increase, we performed a cross-sectional study of men aged 40-79 years using the data from the National Survey of Circulatory Disorders 1990 in Japan. First, we investigated the association between alcohol intake and two types of biochemical variables: serum lipids and blood pressure, by using analysis of variance. Then, concerning the subjects aged 40-59 years, linear regression analyses between alcohol intake and these biochemical markers were done to calculate regression coefficients adjusted for confounding factors. Finally, we substituted these regression coefficients for previously reported regression coefficients in Cox proportional hazard models to calculate relative and absolute risks for coronary heart disease and stroke. Alcohol intake positively correlated to systolic and diastolic blood pressure (SBP and DBP) and high-density lipoprotein cholesterol (HDLC). However, there was no relation between alcohol intake and serum total cholesterol. Linear regression coefficients of SBP, DBP and HDLC were 2.25, 1.43, 2.70, respectively. We used two proportional hazard regression formulas of Japanese population: one for coronary disease (Circulation 89, 2533-39) and the other for stroke (NIPPON DATA80, a 14-year cohort study of randomly selected Japanese). The estimated relative risks of coronary heart disease and stroke were 0.89 and 1.06 for 1 "go" (23 g of ethanol) increment of alcohol intake. The results indicate that the mortality rates shift from 0.44 to 0.39 per 1,000 person-years for coronary heart disease and from 0.76 to 0.81 per 1,000 person-years for stroke in the representative Japanese population aged 40-59 years. The absolute risk of cardiovascular disease may be unchanged if we assume 23 g increment of ethanol intake in Japan because the risk reduction in coronary heart disease was nearly equal to the risk increment in stroke.

To examine the relation of triglycerides with coronary heart disease among populations with low mean total cholesterol, the authors conducted a 15.5-year prospective study ending in 1997 of 11,068 Japanese aged 40-69 years (4,452 men and 6,616 women with mean total cholesterol = 4.73 mmol/liter and 5.03 mmol/liter, respectively), initially free of coronary heart disease or stroke. There were 236 coronary heart disease events comprising 133 myocardial infarctions, 68 angina pectoris events, and 44 sudden cardiac deaths. The coronary heart disease incidence was greater in a dose-response manner across increasing quartiles of nonfasting triglycerides for both sexes. The multivariate relative risk of coronary heart disease adjusting for coronary risk factors and time since last meal associated with a 1-mmol/liter increase in triglycerides was 1.29 (95% confidence interval (Cl): 1.09, 1.53; p = 0.004) for men and 1.42 (95% Cl: 1.15, 1.75; p = 0.001) for women. The trend was similar for myocardial infarction, angina pectoris, and sudden cardiac death. The relation of triglycerides with coronary heart disease was not influenced materially by total cholesterol levels or, in a subsample analysis (51% of total sample), by high density lipoprotein cholesterol levels. Nonfasting serum triglycerides predict the incidence of coronary heart disease among Japanese men and women who possess low mean values of total cholesterol. Further adjustment for high density lipoprotein cholesterol suggests an independent role of triglycerides on the coronary heart disease risk.

To examine the reliability and construct validity of the Japanese version of the Anger Expression Scale among four Japanese communities, and to examine distributions of anger expression scores according to sex, age, occupation, and community, we performed a crosssectional study among 1,802 men and 3,229 women aged 20-70 in four geographic populations in 1995-97. We handed a self-administered questionnaire, which was selected from the Spielberger Anger Expression Scale, to the participants in the risk factor surveys and measured anger-in and anger-out as the anger expression scale. These scales had high internal consistency (Cronbach's alpha coefficient was 0.97-0.98 for anger-out and 0.77-0.86 for angerin) and were of almost the same structure as the original. The Pearson correlation coefficients for the anger expression scale examined in 1995 and 1996 were 0.69 for anger-out and 0.57 for anger-in (both p<0.001). The mean scores of both anger-out and anger-in were inversely associated with age. The mean anger-out score was higher for men than for women (p<0.001), whereas the mean anger-in score did not vary significantly between the sexes. Furthermore, the mean scores of anger-out and anger-in varied among populations and occupational groups. The present study suggests that the Japanese version of the selected Anger Expression Scale is an acceptable scale for evaluatinq anger expression among Japanese.

There is little information on the relation of plasma fibrinogen concentration to the risk of coronary heart disease in Asians, including Japanese, whose plasma fibrinogen concentration has been reported to be low by Western standards. The authors conducted a prospective study with 4.8 years of follow-up of 11,977 men and women aged 21-89 years (mean value of fibrinogen = 267 mg/dl) living or working in Osaka, Japan, in 1990-1996 to examine the relation of plasma fibrinogen with the incidence of coronary heart disease (myocardial infarction and angina pectoris). Mean fibrinogen concentration was 293.6 mg/dl for men who developed coronary heart disease (n = 35) compared with 261.6 mg/dl for men free of coronary heart disease (n = 8,094; difference, p < 0.01), and 355.2 mg/dl for women who developed coronary heart disease (n = 6) compared with 276.8 mg/dl for women free of coronary heart disease (n = 3,842; difference, p < 0.01). With a Cox proportional hazards model to adjust for cardiovascular risk factors, the relative risk for the highest fibrinogen quartile (≥295 mg/dl) compared with the lowest (<228 mg/dl) was 4.8 (95% confidence interval: 1.4, 16.8, p = 0.01) for coronary heart disease, and 3.8 (95% confidence interval: 1.1, 13.4, p = 0.04) for myocardial infarction. Plasma fibrinogen is useful to predict the risk of coronary heart disease among urban Japanese, whose mean plasma fibrinogen is relatively low.

Background: Few prospective data are available to evaluate potential risk factors of subarachnoid hemorrhage among the Japanese, although several prospective studies conducted in the United States and in Europe have shown a positive relationship between alcohol intake and the risk of subarachnoid hemorrhage. Methods: A 9.4 year follow-up study was conducted on 12,372 men and women age 40 to 69 years who had no history of stroke, in six communities in Japan. The incident cases of subarachnoid hemorrhage were confirmed with computed tomography findings and/or clinical findings. Alcohol intake and other cerebrovascular risk factors were measured at the baseline examination. A Cox proportional hazard analysis was used to estimate the relative risks and 95% confidence intervals of the incidence of subarachnoid hemorrhage. Results: During the follow-up assessment, 71 cases of subarachnoid hemorrhages occurred. For men, heavy drinking appeared to be an independent risk factor for subarachnoid hemorrhage; multivariate-adjusted relative risk was 4.3 (95% confidence interval [CI]: 1.1-16.8;p = 0.04). Among women, no excess risk was found for heavy drinking, probably due to the small number of heavy drinkers (n = 15). The combination of heavy drinking with smoking or hypertension increased the risk of subarachnoid hemorrhage substantially for men; the multivariate-adjusted relative risk was 6.0 (95% CI: 1.8-20.1;p = 0.004) for heavy drinking smokers and 13.0 (95% CI: 3.9-43.9; p < 0.001) for heavy drinking hypertensives. Conclusions: A reduction in alcohol intake, smoking cessation, and control of hypertension are important in preventing subarachnoid hemorrhage among Japanese men.

Background: Proteinuria has been considered to be a prognostic marker for persons with diabetes mellitus, but only a limited number of studies about the relationship between proteinuria and mortality among general population has been available. Methods: The subjects were 10,897 individuals who participated in the National Cardiovascular Survey conducted in 1980 and who were aged 30 years or older living in 300 districts that had been randomly selected throughout Japan. The vital records were confirmed in 1999 and 7,203 subjects (3,180 males and 4,023 females) without a history of hypertension, stroke, heart disease, renal disease, or diabetes mellitus at the start of the study were investigated. Results: There were 126,825 person-years of follow-up. During the observed period of time, 371 died of cardiovascular causes, including 171 stroke deaths and 74 coronary deaths. The risk of proteinuria for cardiovascular mortality was greater than unity for those with a normal serum creatinine level, after adjusting for age and other cardiovascular disease risk factors. Conclusions: When contrasted with other cardiovascular disease risk factors, urinary protein is an independent risk factor for cardiovascular death among the Japanese population. Copyright © 2005 by the Japan Epidemiological Association.

Background: Evidence suggests that the predictive value of serum alanine aminotransferase (ALT) levels for prognosis, measured by indices such as all-cause mortality and medical costs, may be modified by body mass index (BMI). However, the relationship between serum ALT and BMI has not been satisfactorily elucidated. Methods: Four thousand, five hundred and twenty-four community dwelling Japanese National Health Insurance beneficiaries, 40-69 years old, were classified into five categories according to their serum ALT levels (IU/L) (ALT<20, 20≤ALT<30, 30≤ALT<40, 40≤ALT<50 and 50≤ALT) and followed for 10 years. Hazard ratios for all-cause mortality, with reference to the lowest serum ALT category, and medical costs per person were evaluated for each serum ALT category after analyzing interactions between serum ALT levels and BMI for all-cause mortality and for medical costs. Results: A significant interaction between serum ALT levels and BMI was observed. In participants below the median BMI, positive, graded relationships were identified between serum ALT levels and all-cause mortality as well as between serum ALT levels and personal medical costs. The multivariate-adjusted hazard ratio in the "50≤ALT" category showed an approximately 8-fold increase. However, in the participants at or above the median BMI, no significant relationships between serum ALT levels and all-cause mortality or personal medical costs were identified. Conclusions: In these Japanese participants, the predictive value of serum ALT levels for prognosis was more evident if BMI was taken into account. A combination of high serum ALT levels and below median BMI was associated with excess mortality and medical cost. Copyright © 2006 by the Japan Epidemiological Association.

Hypertension and related cardiovascular diseases may lead to an increase in medical costs for patients. We attempted to clarify the relationship between hypertension and long-term medical costs by a cohort study utilizing existing data as well as baseline blood pressures and medical costs over a 10-year period. The participants included 4,191 Japanese National Health Insurance beneficiaries aged 40-69 years, living in one area, who were not taking anti-hypertensive medication and did not have a history of major cardiovascular disease. They were classified into four categories according to their blood pressure. We evaluated the mean medical costs per month, cumulative hospitalization, and all-cause mortality for each blood pressure category. Hypertension-related medical costs attributable to hypertensive individuals, as compared to normotensive individuals, were estimated. There was a positively graded correlation between blood pressure and personal total medical costs, especially for men. The odds ratio for cumulative hospitalization and hazard ratio for all-cause mortality in severe hypertensive men were also higher than those in normotensive men. However, the hypertension-related medical costs for mild to moderate hypertensives were higher than those for severe hypertensives. The hypertension-related medical costs for all hypertensives accounted for 23.7% of the total, medical costs for the Japanese population. In conclusion, high blood pressure was a useful predictor for excess medical costs; moreover, concomitant hypertension, regardless of the grade, increased the medical costs of Japanese National Health Insurance beneficiaries.